STATE FARM: TALK TO AN AGENT

Established in 1922, State Farm has become a trustworthy, reliable company that prides itself on the dedication of its agents and their ability to provide personalized insurance policies. Even though State Farm leads the insurance industry, the company is struggling to gain customers in the 18-25 year old demographic. As a part of this demographic, many of us were guilty of quickly purchasing our insurance policies online. We thought that we had the coverage we needed — that was before we talked to an agent. In one hour, local State Farm agent Vincon Krikac changed 25 minds. We learned how little we actually knew and how necessary it is to have an agent. Our peers are no more informed about insurance than we were. Simple questions like, “What’s the difference between liability and collision?” were difficult for them to answer. We knew that if we could give the target audience a glimpse of what we experienced, they would want to talk to a State Farm agent, too. Our research led us to build creative executions that work with media to make our campaign engage the target audience and encourage them to contact a State Farm agent. Our “Talk to an Agent” campaign highlights what the target audience doesn’t know about insurance and illustrates how to fi nd the answers to their questions. This campaign ensures State Farm will remain the market leader in the insurance industry and gain new customers in the 18-25 year old demographic. It works because it illustrates the key benefit of State Farm Insurance—the agent

Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective Na_V1.7 Inhibitors

The majority of potent and selective hNa_V1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNa_V1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this library was elaborated, optimizing for potency and selectivity with attention to physicochemical properties. The resulting novel leads are potent, ligand and lipophilic efficient, and selective over hNa_V1.5. Representative lead <b>36</b> demonstrates selectivity over other human Na_V isoforms and good pharmacokinetics in rodents. The biaryl acyl sulfonamides reported herein may also offer ADME advantages over known heteroaryl sulfonamide inhibitors

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities

Several reports have recently emerged regarding the identification of heteroarylsulfonamides as Na_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V isoforms. The optimization of a series of internal Na_V1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound <b>20</b>, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

Because of its strong genetic validation, Na_V1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of Na_V1.7, which demonstrate nanomolar inhibition of Na_V1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na_V1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity

Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity

Because of its strong genetic validation, Na_V1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as Na_V1.7 inhibitors that demonstrate high levels of selectivity over other Na_V isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation. WO 2014201206, 2014] of Na_V1.7, which demonstrate nanomolar inhibition of Na_V1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound <b>39</b> (AM-0466) demonstrated robust pharmacodynamic activity in a Na_V1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity